The human complement system is a tightly regulated set of ~30 serum or membrane-bound proteins which is best known for its role as a ?first-line-of-defense? against microbial intruders. A modern view places complement at the center of a number of important physiological processes including adaptive immunity crosstalk, developmental roles, and as a critical player in maintaining homeostasis. A large number of human autoimmune, inflammatory, and neurodegenerative diseases are now linked to the loss of the fine-tuned control of the complement cascade. Recently, the dysregulation of the classical complement pathway has been shown to play a causal role in murine models of Alzheimer?s disease. With 5 million Americans currently suffering from Alzheimer?s disease, and a predicted 14 million by 2050, development of new treatments is desperately needed. Unfortunately, the clinical pipeline of complement-directed drugs is currently inadequately positioned to produce therapies for classical pathway-driven neurodegenerative conditions. To meet this need, the fundamental goal of this project is to develop high quality, high specificity small molecule inhibitors of the classical complement pathway. The first component of complement, C1, is the multi-subunit zymogen of the classical pathway and consists a single molecule of C1q in complex with the serine protease heterotetramer C1r2C1s2. C1r is the initiator protease of the pathway and has the unique feature of requiring the molecular context of C1 to carry out its only known physiological function (i.e. activation of the classical pathway). In this project we will attempt to exploit this molecular provision by identifying C1r-binding small molecules which disrupt the stability of C1. To achieve this we will use fragment based drug design and natural product-inspired chemical libraries in combination with an surface plasmon resonance-based screening methodology. We will then implement a novel strategy to isolate compounds with high C1r-specificty and high complement inhibitory potential. Finally, x-ray crystallography will be used to reveal the binding mode of prioritized hit compounds. This project will provide the framework for structure-based drug design efforts for the development of novel complement-directed therapeutics for treatment of classical pathway-related human diseases such as Alzheimer?s disease.